BackgroundAnaphylaxis is an acute systemic reaction with symptoms of an immediate-type allergic reaction which can involve the whole organism and is poten-tially life-threatening [1–3].

� e de� nition of anaphylaxis is not globally uni-form. At present di� erent classi� cation systems are used. In German-speaking countries, the classi� -cation used here has generally been applied until now.

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Guideline

Cite this as: Ring J, Beyer K, Biedermann T, Bircher A, Duda D, Fischer J et al. Guideline for acute the-rapy and management of anaphylaxis. S2 guideline of DGAKI, AeDA, GPA, DAAU, BVKJ, ÖGAI, SGAI, DGAI, DGP, DGPM, AGATE and DAAB. Allergo J Int 2014; 23: 96–112

DOI 10.1007/ 10.1007/s40629-014-0009-1

Guideline for acute therapy and management of anaphylaxisS2 Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Association of German Allergologists (AeDA), the Society of Pediatric Allergy and Environmental Medicine (GPA), the German Academy of Allergology and Environmental Medicine (DAAU), the German Professional Association of Pediatricians (BVKJ), the Austrian Society for Allergology and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), the German Society of Pharmacology (DGP), the German Society for Psycho-somatic Medicine (DGPM), the German Working Group of Anaphylaxis Training and Education (AGATE) and the patient organization German Allergy and Asthma Association (DAAB)JO H A N N E S RI N G1, K I R S T E N BE Y E R 2, TI LO BI E D E R M A N N 3, AN D R E A S BI R C H E R 4, DO R OT H E A DU DA 5, JÖ R G FIS C H E R 3, FR A N K FR I E D R I C HS 6, TH O M A S FU C HS7, UW E G I E L E R 8, TH I LO JA KO B 9, LU D G E R K L I M E K10, L A R S L A N G E11, HA NS F. ME R K12, BO D O NI G G E M A N N13, O L I V E R PFA A R10, BE R N H A R D PR Z Y B I L L A14, FR A N Z IS K A RU Ë FF14, ER NS T RI E T S C H E L15, SA B I N E SC H N A DT16, RO L A N D SE I FE R T17, HE L M U T SI T T E R18, EVA-MA R I A VA R G A19, MA R G I T TA WO R M 20, K N U T BR O C KO W1

1Dept. Dermatology and Allergology Biederstein, Technical University Munich; 2Department of Pediatrics, Division of Pneumonology and Immunology, Charité University Medical Centre, Berlin; 3University Department of Dermatology, Tübingen; 4 Department of Dermatology, University Hospital of Basel, Switzerland; 5Department of Anesthesiology and Critical Care Medicine, University Mainz; 6Pediatric practice Laurensberg, Aachen; 7Department of Dermatology, University Hospital Göttingen; 8Dept. of Psychosomatic Medicine and Psychotherapy, University of Gießen; 9Depart-ment of Dermatology of the University Medical Center Freiburg; 10Center for Rhinology and Allergology Wiesbaden, ENT Dept. University of Mannheim; 11St.-Marien-Hospital Bonn; 12Department of Dermatology, University Aachen; 13DRK Kliniken Berlin Westend, Berlin; 14Department of Dermatology and Allergology, Hospital of the Ludwig Maximi-lians University, Munich; 15Department of Pediatrics, University Hospital Cologne; 16German Allergy and Asthma Asso-ciation, Mönchengladbach; 17Institute of Pharmacology, Hannover Medical School; 18Institute for Surgical Research, Philipps University of Marburg; 19Department of Pediatrics, Medical University of Graz, Austria; 20Department of Der-matology, Venereology and Allergology, Allergie-Centrum-Charité, Charité University Medical Centre, Berlin

Level of development

S2

AWMF-guideline-register-number

061-025

FinalisedDezember 1, 2013

Valid untilApril 2019

CheckApril 1, 2018

ICD-10-numbersT 78, T 80, J.45, L 23

German Versionwww.springer-

medizin.de/ allergo-journal

Anaphylactic reactions are the most severe and potentially life-threatening dramatic conditions seen in allergy. Acute treatment is based on inter-national guidelines and recommendations in text-books. In 1994, a position paper of the German So-ciety for Allergology and Clinical Immunology (DGAKI), was published in the Allergo Journal as the result of an interdisciplinary consensus confer-ence [4]. � is was subsequently updated and pub-lished as a guideline in 2007 [5].

On resolution of the board of directors of the DGAKI of 2009, the anaphylaxis working group was asked to update the guideline. � e members of this working group have met several times, togeth-er with experts from other associations such as al-lergology, anaesthesiology and intensive care med-icine, dermatology, pediatrics, internal medicine, otolaryngology, emergency medicine, pharmacol-ogy, pneumology and theoretical surgery.

In addition to DGAKI members, members of the Association of German Allergologists (AeDA), the Society of Pediatric Allergy and Environmental Medicine (GPA), the German Professional Associa-tion of Pediatricians (BVKJ), the German Academy of Allergology and Environmental Medicine (DAAU), the Austrian Society for Allergology and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), the German Society of Pharmacology (DGP), the German Society for Psychosomatic Med-icine (DGPM), the German Working Group of Ana-phylaxis Training and Education (AGATE) as well as the patient organisation German Allergy and Asthma Association (DAAB) were included. � ere were consensus conferences in Wiesbaden in Sep-tember 2009, in Grainau in March 2011, in Munich in January 2012, October 2012 and December 2012 and � nalizing via electronic mail rounds. � e rec-ommendations worked out at the conferences are based on literature searches with assessment of clin-ical studies, case series, singular case reports, ex-perimental investigations, on participants’ experi-ence as well as on theoretical re� ections. Case series were of greatest importance, whereas theoretical re-� ections in� uenced the assessment only when sin-

gular cases, nor case series or experimental investi-gations could not be used for the evaluation. As a whole, the number of meaningful studies of ana-phylaxis treatment is so low that its management remains empirical in many � elds and is o� en de-rived from pathophysiological re� ections.

Anaphylactic reactions may come to a spontane-ous standstill at any symptomatic stage, but they may also progress in spite of adequate therapy. � is unpredictability makes it di� cult to evaluate the ef-fectiveness of therapeutic measures. Observations of a single case do not allow assessments as to whether speci� c measures were e� ective. It is, how-ever, evident that patients received inadequate fol-low-up care a� er anaphylaxis due to an insect sting [6, 7]. � e fact that basic patient care is suboptimal underlines the need for more research as well as the importance of the present guideline.

� is guideline is for all doctors and other persons working in the medical � eld who are concerned with acute treatment, diagnostics and counselling of patients with anaphylaxis.

Epidemiology of anaphylaxisSince anaphylaxis was � rst described [8], there have been few exact epidemiological studies on the fre-quency (prevalence and incidence) of anaphylactic reactions. Because of the non-uniform de� nition (see below), a considerable number of undetected cases must be assumed.

A limitation of the data on the epidemiology of anaphylaxis is due to the non-uniform ICD-10 cod-ing terms of anaphylaxis. � ere are numerous ICD-10 coding terms that may include anaphylaxis. In addition, the de� nition of anaphylaxis is globally non-uniform [9]. It has to be clari� ed in particular whether recurrent cutaneous reactions due to type I allergy should already be considered as anaphy-laxis, whether participation of at least two organ systems should be present per de� nition or whether only the involvement of the organs of the respirato-ry and cardiovascular systems represent a severe re-action that should be regarded as anaphylaxis. At present there is neither national nor international consensus regarding this. Published data regarding epidemiology must therefore be evaluated in con-sideration of these aspects [10].

Retrospective studies suggest that up to 1 % of pa-tients present to the emergency department of a maximum care hospital because of an anaphylactic reaction [11]. One to three anaphylaxis-induced fa-talities per year per 1 million inhabitants are esti-mated [12].

� ere are up-to-date studies from the USA, Great Britain and Australia on the epidemiology of ana-phylaxis. � ey show incidence rates of anaphylaxis of between 7 to 50 per 100,000 / year [13–15]. � ese

Allergo J Int 2014; 23: 96−112 97

Abbreviations

ACE Angiotensin-converting enzyme

FiO2 Fraction of inspired oxygen

HES Hydroxyethyl starch

NaCl Sodium chloride

NSAID Nonsteroidal anti in� ammatory drugs

numbers imply an increase in anaphylaxis over the last few decades, the cause being unclear. Numbers from the anaphylaxis register of the German-speak-ing countries and also data from other countries in the world show that foods are the most frequent triggers of anaphylaxis in childhood [10]. Insect venoms as well as drugs are the most frequent trig-gers in adults in Germany (Tab. 1), whereby inter-nationally the order varies. In childhood, boys suf-fer anaphylaxis more frequently than girls with dis-tribution adaptation between the genders occuring a� er puberty [16].

Pathophysiology� e symptoms of anaphylactic reactions are caused by release of di� erent mediators (e.g. histamine, prostaglandins, leukotrienes, tryptase, platelet-ac-tivating factor, cytokines, chemokines) from mast cells and basophil granulocytes [17–19], the individ-ual signi� cance of each of these is not assessed clear-ly in detail. However, there is a consensus that his-tamine plays a central role in anaphylactic reactions.

� e pathomechanism of anaphylaxis usually rep-resents an immunological reaction, most o� en an immunoglobulin E mediated allergy. However, spe-ci� c antibodies of other classes can trigger similar complement-dependent symptoms through the for-mation of circulating immune complexes (immune complex anaphylaxis) [20].

� ere are also a high number of anaphylactic re-actions where no immunological sensitization is de-tectable; these reactions are called „pseudo-allergic reactions” [20] or recently „non-allergic anaphylax-is“ [1]. � e mechanisms of this non-allergic anaphy-laxis comprise G protein-induced, direct release of vasoactive mediators, direct activation of the com-plement system, interactions with the kallikrein-ki-nin system, interactions with arachidonic acid me-tabolism as well as psychoneurogenic re� ex mecha-nisms. Knowledge on the pathophysiology of these reactions is much more limited than on allergic ana-phylaxis.

In patients with increased basal serum tryptase and/or mastocytosis, anaphylaxis may be particu-larly severe [21–23].

Preceding intake of β-adrenoceptor antagonists and ACE inhibitors can lead to a deterioration of the anaphylactic symptoms [24]. For β-adrenoceptor antagonists, blocking of the cardiostimulatory ef-fect of adrenaline as well as its mast cell-stabilizing e� ect play a role, and, in the case of ACE inhibitors, reduced bradykinin clearence with resulting marked vasodilatation. Also the intake of nonste-roidal anti-in� ammatory drugs (NSAIDs) can re-sult in severe anaphylactic reactions due to in-creased leukotriene formation and facilitated ab-sorption of ingested allergens.

Clinical SymptomsAnaphylactic reactions essentially manifest on the skin, in the respiratory tract, gastrointestinal tract, and cardiovascular system. � e working group has discussed whether the guideline should be based on a severity classi� cation, as the treatment of ana-phylaxis is symptom-related. � e majority voted for a severity classi� cation. � ere are di� erent severity classi� cations in the literature [7, 9, 25, 26]. Each severity classi� cation has advantages and disad-vantages. � e majority of the group opted to mod-ify the severity classi� cation which is most fre-quently used in Germany at present [26]. Anaphy-laxis is classi� ed by degrees of severity from I–IV, depending on the intensity of the clinical symp-toms (Tab. 2).

� e symptoms of anaphylactic reactions usually begin acutely and may progress very quickly. � us, symptoms can deteriorate within minutes resulting in death. � e reaction may, however, also come to a spontaneous standstill at any stage and regress spontaneously. In a reaction of grade I severity, the further development and dynamics of the reaction are primarily not foreseeable. � e symptoms may occur either simultaneously or sequentially. � ere may be primarily circulatory reactions without pre-ceding cutaneous or respiratory signs. Occasionally there are protracted or biphasic courses with recur-rent symptoms 6–24 hours a� er successful initial therapy [27]. Apart from acute onset of symptoms and biphasic courses, delayed anaphylactic reac-tions may occur where symptoms only begin some hours a� er exposure. � e most striking example of this particular dynamic has been documented for the allergen galactose-alpha-1,3-galactose in mam-malian meat allergy and is probably based on de-layed release or systemic availability of allergens or their binding sites [28].

At the beginning of an anaphylaxis, minor pro-dromal symptoms or signs can appear, like itching or burning of the palms and soles or in the genital area, a metallic taste, fearfulness, headache or dis-orientation. Young children cannot speci� cally ex-press these feelings and they may present with symptoms such as restlessness or withdrawal behav-iour even before the occurrence of objective signs.

| Table 1Common elicitors of severe anaphylactic reactions in children and adults [10]

Elicitor Children AdultsFood 58 % 16 %Insect venoms 24 % 55 %Drugs 8 % 21 %

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Guideline Acute therapy and management of anaphylaxis

In anaphylaxis most o� en the skin and mucous membranes are a� ected with pruritus, erythema (� ush) as well as urticaria and angioedema (Quincke’s edema). � ese may occur in areas of the skin having had no direct contact with the trigger (systemic spread).

In the upper respiratory tract, patients o� en de-scribe burning, tingling or itching of the tongue or palate as early symptoms. In the oropharynx, swelling of uvula and tongue can be observed. Clinical signs are a mu� ed voice, dysphagia with salivation or inspiratory stridor. � e possible con-sequences of laryngeal edema are airway obstruc-tion with life-threatening hypoxia within a short time period.

In the lungs, in particular patients with asthma can develop bronchoconstriction and dyspnoea. Clinical signs are wheezing, prolonged expiration and increased respiratory rate. Bronchial obstruc-tion is the leading symptom in life-threatening re-actions especially in children and adolescents. � e degree of asthma correlates directly with the sever-ity of the anaphylactic reaction. Also to a variable extent vasoconstriction can occur, at times result-ing in an extreme increase in pulmonary vascular resistance, respiratory arrest and the need for re-suscitation. Pulmonary edema can also occur as a consequence of this permeability disturbance [29–32].

Gastrointestinal symptoms include crampy ab-dominal pain, nausea, vomiting and diarrhea. � ere may also be increased intestinal motility with me-teorism, the urge to defecate and even involuntary defecation. Further abdominal symptoms consist of the urge to urinate, micturition as well as uterine cramps. In children, mild oral symptoms or peri-oral reddening with vomiting may be the only symptoms of food-induced anaphylaxis.

Because of vasodilatation and increased vascular permeability, � uid loss into the extravascular space occurs leading to hemoconcentration and hypovo-lemia, followed by arterial hypotension and tachy-cardia. Direct cardiac symptoms include arrhyth-mia, bradycardia or myocardial infarction.

Central nervous system symptoms are restless-ness, withdrawal behaviour, headache, seizures, impaired and loss of consciousness. In children, a change in behaviour is o� en observed, expressed by anxiety or sometimes aggression. Older chil-dren, adolescents and adults can experience “a sense of impending doom”.

In particular the causes of fatal anaphylaxis are airway obstruction and/or cardiovascular failure, either due to direct cardiac involvement or as a con-sequence of the microcirculatory dysfunction with shock; rare causes are disseminated intravascular coagulation or adrenaline overdose [32].

Allergens and triggers� e most frequent triggers of severe anaphylactic re-actions are drugs, insect venoms and foods. � e ranking of the triggers depends on age and circum-stances. In children, foods are very frequent triggers, whereas for adults insect stings or drugs (including preparations for allergen-speci� c immunotherapy and chemotherapeutic agents) are more o� en men-tioned (Tab. 1).

� e contact with the anaphylaxis trigger most fre-quently occurs via the oral or parenteral/hematog-enous route. In strongly sensitized persons, anaphy-laxis can also be triggered by air-borne allergens or by application to the skin surface [33].

Anaphylactic symptoms can also occur depend-ing on the combination of various factors, e.g. al-lergen exposure together with physical exertion (“exercise-induced anaphylaxis”) [34], alcohol, mental stress or emotional stress, acute infections or simultaneous exposure to other allergens as well as concurrent intake of anaphylaxis-enhancing drugs. � is phenomenon is called “augmentation” or “summation” anaphylaxis. A more common form is food-dependent exercise-induced anaphy-laxis (FDEIA), which is most frequently triggered by wheat � our [35].

Risk factors for severe anaphylaxis� ere are several risk factors for severe (grade III and grade IV) anaphylaxis. Risk factors which exist independent of the trigger are high age [16], severe cardiovascular diseases, pre-existing and in partic-ular poorly controlled bronchial asthma, intake of drugs promoting mast cell activation or leukotriene formation (e.g. NSAID) and mastocytosis. For in-sect venom allergy, the intake of β-adrenoreceptor antagonists and ACE inhibitors, physical and psy-

| Table 2Severity grading of anaphylactic reactions (modi� ed according to [26])GradeGrade SkinSkin AbdomenAbdomen AirwaysAirways Cardiovascular systemCardiovascular systemI Itch

FlushUrticariaAngioedema

–– –– ––

II ItchFlushUrticariaAngioedema

NauseaCramps

RhinorrheaHoarsenessDyspnea

Tachycardia (> 20/min)Hypertension (> 20 mm Hg syst.)Arrhythmia

III ItchFlushUrticariaAngioedema

Vomiting Defecation

Laryngeal edemaBronchospasmCyanosis

Schock

IV ItchFlushUrticariaAngioedema

Vomiting Defecation

Respiratory arrest Cardiac arrest

Classifi cation according to the most severe symptom, no symptom is mandatory.

Allergo J Int 2014; 23: 96−112 99

chological stress as well as an increased basal serum tryptase are also mentioned [24].

In consideration of the trigger-related subgroups of anaphylaxis, there are data for food anaphylaxis showing that here again allergic bronchial asthma is an important risk factor [36]. � e speci� c trigger may in itself act as a risk factor; it is known, for ex-ample, that peanut as a potent allergen is a risk fac-tor for severe reactions [37].

Diagnosis and important di� erential diagnoses� e clinical symptoms of anaphylaxis are not always characteristic so that diagnosis may be di� cult. In these situations it is especially important to distin-guish other conditions from symptoms of an ana-phylactic reaction, e.g. other triggers of isolated ur-ticaria, airway obstruction, vomiting, nausea, diar-rhea, restlessness, unconsciousness, cardiac ar-rhythmia or cardiac arrest. Important di� erential diagnoses are listed in Tab. 3. A� er adequate acute treatment, it is helpful to measure mediators in the

blood, above all serum tryptase, ideally about one to three hours a� er the onset of anaphylaxis and – if possible – a comparison to basal serum tryptase should be made. Serum tryptase can also be mea-sured at a later time, even post mortem [38, 39].

In a consensus conference, the following symp-toms were regarded as being of speci� c importance for the diagnosis of anaphylaxis [9]:

—Sudden occurrence of symptoms on the skin (e.g. acute urticaria, angioedema, � ush, swelling of mucous membranes) in addition to rapid onset respiratory symptoms (e.g. dyspnoea, wheeze, cough, stridor) or a sudden blood pressure drop or clinical manifestations thereof (e.g. collapse, tachycardia, incontinence) or —Sudden occurrence of symptoms in two or more of the following organs or organ systems: skin (e.g. acute urticaria, angioedema, � ush, swelling of mucous membranes), gastrointestinal tract (e.g. abdominal cramps, vomiting), respiratory tract (e.g. dyspnoea, wheezing, cough, stridor) or cir-culatory system (e.g. hypotension, collapse, in-continence) a� er contact with a probable allergen or anaphylaxis trigger or —Hypotension following contact with an allergen known to the patient or another anaphylaxis trig-ger.

Pharmacology of the most important drugs in anaphylaxis treatmentIn speci� c pharmacotherapy, the following sub-stances have proven to be e� ective:

Vasoactive substancesAdrenaline: � e most important drug in the acute therapy of anaphylaxis is adrenaline (epinephrine). � rough the activation of α- and β-adrenergic re-ceptors, adrenaline functionally antagonises all of the important pathomechanisms of anaphylaxis by vasoconstriction, reduction of vascular permeabil-ity, bronchodilatation, edema reduction and posi-tive inotropy in the heart. Administered intrave-nously, it shows the fastest onset of action of all ana-phylaxis drugs.

In a patient not in need of resuscitation, immedi-ate intramuscular application of a dose of 0.3 to 0.5 mg adrenaline (body weight range 30 to 50 kg) to the outer upper thigh is the drug therapy of � rst-choice. Compared with intravenous application, the risk of severe cardiac side e� ects is considerably lower. In case of no response, the injection can be repeated ev-ery 5–10 minutes, depending on side e� ects.

Subcutaneous injection of adrenaline is no longer recommended because of insu� cient absorption re-sulting in delayed onset of action.

If the patient is unstable or during resuscitation, i.e. in case of respiratory and/or circulatory arrest,

| Table 3Relevant di� erential diagnoses of anaphylaxis

Cardiovascular diseases

— Vasovagal syncope

— Cardiogenic shock

— Cardiac arrhythmia

— Hypertensive crisis

— Pulmonary embolism

— Myocardial infarction

Endocrinological diseases

— Carcinoid syndrome

— Pheochromocytoma

— Thyrotoxic crisis

— Hypoglycemia

Neuropsychiatric diseases

— Hyperventilation syndrome

— Anxiety/panic attacks

— Dissociative disturbances and conversion disorders(e.g. globus hystericus)

— Psychoses

— Factitious disorders (Münchhausen syndrome)

— Somatoform disturbances (e.g. psychogenic dyspnea, „vocal cord dysfunction“)

— Epilepsy

— Coma (e.g. metabolic, traumatic)

Respiratory diseases — Status asthmaticus (acute severe asthma without involve-ment of other organs)

— Acute obstructive laryngo-tracheitis

— Tracheal/bronchial obstruction (e.g. foreign objects)

Skin diseases — Urticaria and hereditary/ acquired angioedema

Note: in physical urticaria extensive exposure to the respective elicitor can induce anaphylaxis

Pharmacologic/ toxic substances

— Ethanol

— Histaminosis (e.g. scombroid poisoning)

— Opioids (morphine)

— Hoigné-Syndrome

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adrenaline should be applied intravenously [40]. For this, a dilution of 1 mg adrenaline in 10 ml NaCl 0.9 %, i.e. a solution of 0.1 mg/ml is administered, depending on e� ects and side e� ects, under contin-uous control of circulatory parameters. A continu-ous infusion of approx. 0.05–1 µg/kg/minute is equally e� ective. Control of pulse and blood pres-sure is mandatory. In patients receiving treatment with β-adrenoreceptor antagonists and not re-sponding to the repeated injection of adrenaline or other vasoactive substances (see below), adminis-tration of glucagon is recommended [41]. Glucagon, however, only has an e� ect on cardiac symptoms.

Additional inhalation of adrenaline a� er intramus-cular application is e� ective in the case of laryngeal edema and also in bronchospasm. For this purpose, administration of adrenaline (e.g. 2 ml of 1 mg/ml) given with oxygen through a nebuliser and respira-tory mask is recommended. Application of inhaled adrenaline cannot replace parenteral administration.

In the case of mainly bronchial obstruction, ad-ditional administration of an inhalative β-adreno-receptor agonist, e.g. salbutamol or terbutaline, at a dose of 2–4 pu� s, is e� ective. A spacer device should be used in order to improve the e� cacy of inhala-tion when using an aerosol spray.

In the past, in case of hypotension during preg-nancy, administration of ephedrine instead of adrenaline was sometimes recommended. � ere is, however, even less information on ephedrine than on adrenaline. � erefore we also recommend – in agreement with other authors – the application of adrenaline for anaphylaxis during pregnancy [42].

Even when adrenaline is adequately applied, treatment failure or side e� ects can be observed. � e increase in cardiac output leads to elevated ox-ygen consumption and can be arrhythmogenic, so that, in patients with coronary heart disease, the in-travenous application of adrenaline may cause an-gina pectoris or a myocardial infarction. In case of severe life-threatening anaphylaxis there is no ab-solute contraindication for adrenaline. � e indica-tion should, however, be carefully considered in pa-tients with pre-existing heart disease.

Other vasoactive substancesDopamine, noradrenaline and vasopressin are ap-plied in life threatening situations by emergency doctors and under intensive care conditions with continuous monitoring of vital signs.

Dopamine: A favourable action pro� le for the treat-ment of cardiovascular reactions is o� ered by dopa-mine which a� ects α and β adrenoreceptors and has a short half-life. Dopamine leads in low doses, via vascular D1 dopaminergic receptors, to vasodilata-tion in the renal, mesenteric and coronary vascular

bed [43, 44]. At higher concentrations, the blood pressure reducing e� ect by stimulation of the α and β1 receptors prevails. Bronchodilatation also occurs through activation of the β2 adrenoceptor. It is, however, less marked than with adrenaline because dopamine is only a partial β2 adrenoceptor agonist. If adrenaline and volume substitution are insu� ci-ent to control symptoms, dopamine can be admi-nistered as a continuous intravenous infusion instead of adrenaline. � e usual dose is 2–15 µg/kg/minute. Application of dopamine is bound to pulse and blood pressure monitoring. Dopamine is used above all in patients that are receiving treatment with β adrenoreceptor antagonists.

Noradrenaline: Noradrenaline is a potent α und β1 adrenoceptor agonist and stimulates the β2-adrenoceptor to a lesser extent than adrenaline so that, at a therapeutic dose, the bronchodilatatory ef-fect is lower. � erefore an increase in peripheral re-sistance and systolic blood pressure prevails. � ere is little e� ect on the lung. Noradrenaline is used es-pecially when the e� ect of volume substitution and adrenaline/dopamine is insu� cient [45, 46]. Due to its marked vasoconstrictive e� ect, it should be ad-ministered only as a continuous intravenous infu-sion under strict blood pressure and pulse monito-ring. � e usual dose is 0.02–0.15 µg/kg/minute.

Vasopressin: In anaesthesiological literature, the application of vasopression for the treatment of se-vere hypotension is described [47].

OxygenIn case of manifest cardiovascular or pulmonary re-actions, immediate supply of oxygen via an oxygen mask with reservoir bag, is recommended. Admin-istration of high � ow 100 % oxygen is recommended. A laryngeal mask or a laryngeal tube can be helpful. Only in rare cases will endotracheal intubation by an experienced physician (usually emergency physi-cian, anaesthesiologist) become necessary.

Volume substitutionAn important pathophysiological aspect of anaphy-laxis is the resulting hypovolemia which is treated with adequate volume substitution [48–51]. For se-vere anaphylactic reactions, the supply of large amounts of � uid within a short time is necessary. � is can only be achieved through large-bore ve-nous access. If intravenous access is not possible, a special intra-osseous needle can be inserted prefer-ably into the tibia. In case of anaphylactic shock, a supply of 0.5–1 liters, and possibly up to 2–3 liters of � uid – depending on the response – in a very short time is required for adults, for children ini-tially 20 ml/kg body weight.

Allergo J Int 2014; 23: 96−112 101

Primarily, normal saline (NaCl 0.9 %) or balanced electrolyte solutions should be used. When large quantities of electrolyte solutions are given, they re-main in the intravascular space for a short time only. � erefore, failing stabilization a� er the application of larger volumes of electrolytes (> 1 l) the addition-al application of colloid volume substitutes can be considered.

Gelatine and dextran solutions are – in spite of their positive qualities – to be viewed cautiously be-cause of their histamine-liberating potential and the possibility of themselves triggering anaphylaxis (e.g. dextran without pretreatment with low-molec-ular hapten dextran).

Hydroxyethyl starch (HES) preparations, such as mean-molecular weight HES (HES 6 % 200/0.5) are the most commonly used volume substitutes in ana-phylactic shock. Deposits in the reticular endothe-lial system have been observed a� er infusion of more than 1.5 l HES 200/0.5 in adults [48]. For emergency or intensive care use in unstable circu-latory situations hypertonic, hyperoncotic solutions or mean-molecular weight HES 130/0.4 in 6 % solu-tion are also available. For short-term infusions the risk of an possible renal insu� ciency is low [52]. In recent literature the use of colloidal volume substi-tutes, compared with crystalline solutions in the acute treatment of shock conditions is being dis-cussed more and more critically [53].

Antihistamines H1 receptor antagonists� e central role of histamine as a mediator of aller-gic reactions and the e� cacy of H1 antagonists in acute urticaria or rhinoconjunctivitis are evident. � eir e� ects on circulatory parameters and bron-choconstriction, however, are poorly documented [54]. Compared to adrenaline, antihistamines show a slower onset of action; however, they show a favor-able bene� t/side e� ect pro� le in a broad range of in-dications. An e� ect upon the allergic reaction can be assumed and therefore, antihistamines should be given early in all anaphylactic reactions in order to block the e� ects of histamine.

� e only H1 antihistamines registered for intra-venous application in the acute treatment of ana-phylaxis are the � rst-generation substances di-metindene (0.1 mg/kg bw) and clemastine (0.05 mg/ kg bw) with their well-known sedating side e� ects. O� cially the maximum licensed dose of oral anti-histamines is recommended. � e expert group, however, had a consensus that in single selected cases higher doses (up to a maximum of the four-fold dose of the respective substance) can be given, as has been recommended for the treatment of chronic urticaria [55]. In higher doses antihista-mines, however, can exert anticholinergic e� ects leading to tachycardia, dry mouth, gastrointestinal

atony, urinary retention, an increase in ocular pres-sure up to acute glaucoma attack as well as irritabil-ity and paradoxical excitability [56]. � ese symp-toms should be kept in mind.

H1 antihistamines of the second generation are not currently licensed for the treatment of anaphy-laxis and are not available for intravenous injection. In spite of this for emergency oral treatment, the newer more selective H1 antagonists are o� en rec-ommended; in placebo-controlled skin test studies they have shown a rapid onset of action [54]. Fur-ther studies with newer H1 antihistamines for the treatment of anaphylaxis should be performed. In particular intravenous preparations of modern non-sedating H1 antagonists would be helpful.

� ere is little evidence supporting the e� cacy of H2 receptor antagonists in the treatment of acute anaphylactic reactions. One study reported a reduc-tion of cutaneous symptoms a� er additional appli-cation of ranitidine compared with H1 antagonists alone in the treatment of anaphylactic reactions [57]. � e prevention of hypersensitivity reactions by ad-dition of H2 receptor antagonists is better document-ed; however, this e� ect was not analyzed indepen-dently from other given medication [58, 59]. � ere are single case reports for ranitidine in the treatment of anaphylactic reactions [60]. We recommend the additional application of H2 receptor antagonists in severe and treatment-resistant anaphylaxis, since although there is only limited evidence regarding e� cacy, there are no major side e� ects to be expect-ed [61].

GlucocorticosteroidsDue to their slow onset of action, glucocorticoste-roids play a minor role in the acute phase of anaphy-laxis treatment [62]. � ere are no systematic clini-cal trials regarding this indication. However, gluco-corticosteroids are e� ective in the treatment of asth-ma and against protracted or biphasic anaphylactic reactions. An unspeci� c membrane stabilizing ef-fect within the � rst 10–30 minutes of application of high dose glucocorticosteroids (500–1,000 mg) in-dependent of the potency of the glucocorticoste-roids has been postulated in review articles [2,4,62]. When there is no intravenous catheter, glucocorti-costeroids may be applied rectally, especially in small children (e.g. prednisolone suppositories) or orally.

Treatment� e emergency, symptom-orientated treatment of anaphylaxis has to be carried out rapidly. A dia-gram illustrating the treatment steps for physi-cians and the emergency team has been published and is updated in the development of this guide-line (Fig. 1) [63].

102 Allergo J Int 2014; 23: 96−112

Guideline Acute therapy and management of anaphylaxis

Cardiopulmonary Resuscitation

i.v. catheter

Automatic defibrillator

i.v. / i. ossary catheter

Adrenaline i.m. oxygen inh.

Symptom-oriented positioning

Prescribe emergency set, instruct in adrenaline autoinjector use, refer to allergist for further diagnosis and treatment Discharge

Cardiac/circulatory arrest

Hypotension, shock,

unconciousness

Dysphonia, uvula swelling,

inspiratory stridor

Nausea, abdominal colic,

vomiting

Pruritus, flush, urticaria,

angioedema

Dyspnoea, bronchial

obstruction

Other leading symptom

Persistant shock,

unconciousness

Persistant laryngeal edema

Persistant nausea, abdominal

colic, vomiting

Similar subsiding symptoms

Persistant bronchial

obstruction

Adrenaline i.m. / i.v., β2-sympatho-

mimetics s.c. / i.v.

Forced Volume substitution i.v. / i. ossary

Secure airways

Oxygen inh.

Adrenaline inh.

β2-sympatho- mimetic

inh.

Adrenaline i.v. / i. ossary

Glucocorticosteroid i.v.

Dimetindene i.v.

Basic physical examination

Grade IV

Grade II or III

Grade II or III

Grade I

Grade II or III

Grade II or III

Define severity and leading major symptoms

Anaphylaxis

Basic physical examination – severity scoring (I–IV)

Additional therapy

Therapy escalation

Therapy escalation

No escalation

Therapy escalation

Therapy escalation

Define leading symptom and assess indication for further therapy

Adrenaline

i.v. / i. ossary (or i.m.)

Consider coniotomy

Consider

antiemetics/ spasmolytics i.v.

Consider other

catecholamines i.v. / i. ossary

Surveillance

Choose appropriate leading symptom of Initial therapy level

and complete specific measures

not yet applied

Consider securing the airway

(under anesthesia)

Stop allergen contact Call for help

Fig. 1: Regimen of acute anaphylaxis treatment

Allergo J Int 2014; 23: 96−112 103

At � rst further allergen exposure should be stopped if possible. In some situations (e.g. intrave-nous infusion) this can be done easily without los-ing time. � e application of a tourniquet and/or the subcutaneous injection of epinephrine surround-ing a local allergen depot (e.g. a wasp sting or injec-tion site of speci� c immunotherapy) is no longer recommended due to the limited therapeutic ben-e� t and risk of losing time for more important mea-sures. Further assistance should be called in order to guarantee adequate medical care. Each physician should have emergency equipment for the treat-ment of anaphylactic reactions (Tab. 4) in his prac-tice. A teamapproach with the opportunity to del-egate procedures is advisable.

First, a quick history and basic physical examina-tion have to be done (Fig. 1). � is includes:

—Check of vital signs (spontaneous movements and breathing) —Evaluation of pulse and blood pressure (strength, frequency, regularity) —Evaluation of breathing (dyspnea on speaking, in-spiratory or expiratory stridor, wheezing, option-al: auscultation, measurement of the peak � ow us-ing a mechanical peak � ow meter, pulse oxime-try), —Inspection of visible skin and mucous mem-branes, —Questioning for further complaints, e.g. nausea, impulse to vomit, headache, sternal pressure, dis-turbance of vision, pruritus), —Questioning for known allergies.Regarding vital parameters, possible alarm values

are listed in Tab. 5. � ese examinations should be repeated regularly in the course of acute manage-ment.

Smaller children can initially be examined in the arms of the parents. It is important to calm the child and the parents in order to allow adequate exami-

nation and treatment. When the child is � dgety, in-spection of the mouth or auscultation may be di� -cult or even impossible. Irritation by the use of a spatula may increase airway obstruction and should be avoided. Clinical signs of airway obstruction like prolonged expiration, in- or expiratory stridor, wheezing, salivation, retraction of the thoracic wall and constriction nasal alae should be looked for.

Evaluation of severityBased on the examination the degree of severity of the anaphylaxis should be evaluated and the most threatening symptom of anaphylaxis identi� ed (Fig. 1). � e most life-threatening symptom of ana-phylaxis should be treated with priority. � is may lead to 6 possible scenarios:

—Anaphylaxis with cardiac or circulatory arrest (anaphylaxis grade IV) —Anaphylaxis with predominant cardiac and cir-culatory reaction (anaphylaxis grade II/III) —Anaphylaxis with predominant obstruction of upper airways (anaphylaxis grade II/III) —Anaphylaxis with predominant obstruction of lower airways (anaphylaxis grade II/III) —Anaphylaxis with predominant gastrointestinal involvement (anaphylaxis grade II) —Anaphylaxis with systemic generalized skin man-ifestations and subjective symptoms (anaphylax-is grade I).

PositioningImmediately a� er examination, the patient should be positioned according to symptoms. Horizontal positioning and avoidance of further physical exer-cise (walking or trying to sit up) are the basic strat-egies. Depending on the situation the positioning can be varied. Getting up and physical exercise should be avoided because of possible further ag-gravation of anaphylaxis (as with co-factors). When consciousness is impaired especially in a preclinical situation, the recovery position is preferred. For im-provement of the hemodynamic situation the pa-tient may be placed in the Trendelenburg position (elevated legs). In situations with predominant re-spiratory symptoms a (half) sitting position is pref-erable. In the treatment of children actions should not be forced in order to avoid increasing distress.

Anaphylaxis with cardiac or circulatory arrestCardiopulmonary resuscitation with cardiac mas-sage and aided ventilation in a ratio of 30 :2 must be started (Fig. 1). An automatic de� brillator should be connected. And in case of ventricular � brillation early de� brillation has to be initiated. For further pharmacotherapy an intravenous or intraosseous catheter is mandatory. Intravenously applied adren-aline is the substance of choice. 1 ml adrenaline

| Table 4Emergency equipment for treatment of anaphylactic reactions Stethoscope, blood pressure monitorStethoscope, blood pressure monitorTourniquet, syringes, in-dwelling catheter, infusion setOxygen with mask/nasal cannulaGuedel-tube, bag valve mask, suction unit, intubation setAdrenaline for injectionH1 antihistamines for intravenous injection Infusion solutions (0.9 % NaCl solution, balanced electrolytes/ colloids)Glucocorticosteroids for intravenous injection Bronchiodilator (rapidly acting β2 adrenoreceptor agonist for inhalation or intravenous injection)Automatic external defi brillator (optional)Pulse oximeter (optional)

104 Allergo J Int 2014; 23: 96−112

Guideline Acute therapy and management of anaphylaxis

(1 mg/ml) is diluted in a ratio of 1 : 10 to a volume of 10 ml (0,1 mg/ml) and given as a 1 mg bolus (= 10 ml) in 2–5 minute intervals until circulation is sta-bilized. For su� cient oxygenation the airway must be secured. � is can be done via endotracheal intu-bation. Alternatively a laryngeal mask or a larynge-al tube or a combined tube can be used depending on the experience of the physician.

� e � ow of the inspiratory oxygen (FiO2) should be above 0,8. For this, the application of high-� ow oxygen with a reservoir bag is necessary. Based on the pathophysiology of anaphylaxis, forced volume substitution and high dose anti-allergic treatment (antihistamines, glucocorticosteroids) are manda-tory for the correction of hypovolemia and success-ful resuscitation. Immediate transfer to an intensive care unit is advisable (Tab. 6).

Anaphylaxis with predominant cardiovascular reaction� e immediate action is intramuscular injection of epinephrine, especially when there is no intrave-nous catheter (Fig. 1, Tab. 6). Epinephrine autoin-jectors for self-treatment of patients can be helpful in such situations due to their rapid application. � e standardized adrenaline autoinjector doses of be-tween 0,3 mg and 0,15 mg are feasable. When the response is insu� cient a further intramuscular in-jection of epinephrine can be repeated a� er approx. 5 minutes.

� e application of oxygen with the aim to increase the inspired oxygen content (FiO2) above 0,5 is rec-ommended. � is can be achieved using an oxygen mask with a reservoir bag; a nasal cannula has only a limited e� ect on FiO2.

In all forms of altered consciousness, the patient may vomit and this should be accounted for when positioning. � e mouth can be opened with the Es-march hand maneuver and the oral cavity inspect-ed for vomitus that should be removed. A suction unit is helpful.

For further treatment an intravenous catheter is mandatory (Tab. 6). Failing this, an intraosseus catheter is indicated. � e major therapeutic goal is the correction of a relative hypovolemia. Forced vol-ume substitution of an electrolyte solution (5–10 ml/kg bw within 5 minutes) is mandatory. � e applica-tion of such volumes requires a large bore intrave-nous cannula (> 8 Gauge) or several venous cathe-ters. � e application of colloidal volume substitutes in the phase of forced volume substitution is a com-mon emergency medical measure.

Antiallergic substances (antihistamines [beware of anticholinergic side e� ects] and glucocorticoste-roids) should be used in high doses (Tab. 6). In per-sisting or imminent shock the fractionated intrave-nous/interosseus or intramuscular application of

adrenaline is indicated. Continuous monitoring of blood pressure and pulse are necessary. Other sym-pathomimetic substances like dopamine or nor-adrenalin may be given as a continuous infusion via a pump system under monitoring of experienced physicians.

Anaphylaxis with predominant obstruction of the upper airwaysTypical signs are due to swellings in the region of the upper airway. � is can present with a clinically visible swelling of the tongue or uvula, dysphonia or inspiratory stridor. � ese situations can be life-threatening due to obstruction of the larynx. Im-mediate measures in this case are the intramuscu-lar injection of adrenaline and application of oxy-gen (Fig. 1). � e administration of inhaled adrena-line is indicated (Tab. 6, Tab. 7). In the case of insuf-� cient response to these therapeutic measures, co-niotomy may be required.

Anaphylaxis with predominant bronchial obstructionBroncial symptoms belong to the most common symptoms of severe anaphylaxis. In all potentially life-threatening situations the immediate intramus-cular application of adrenaline is indicated. Also topical bronchodilatory treatment is of central im-portance (Fig. 1). Several short acting β2 sympatho-mimetics (e. g. salbutamol, terbutaline) are available for the treatment of bronchial obstruction (Tab. 6, Tab. 7).

It must be considered that some anaphylaxis pa-tients are not experienced in inhalation therapy and may need the help of a spacer device in the case of aerosol sprays or continuous aerosol application (aerosol masks with a pressure/oxygen attachment or electric nebulizers). In the meantime practical battery-based spray nebulizers are available which can be used in paramedical and preclinical situa-tions. Should more intensive therapy be required the intravenous application of adrenaline or inject-able β2 sympathomimetics (terbutaline s. c. or re-proterol i. v.) are possible (Tab. 6). In the case of sta-

| Table 5Possible alarm thresholds for vital parameters* Alarm thresholds Alarm thresholds depending on age

upto 1 year 1–5 years 6–14 years > 14 years

Pulse rate (/min) > 160 > 130 > 120 >110Blood pressure (systolic, mmHg)

< 50 < 60 < 60 < 70

Respiratory rate (/min) > 40 > 35 > 30 > 25Oxygen saturation (%) < 92 < 92 < 92 < 92

* These values show a high individual variability and should only be regarded as approximate information. There are no studies from larger cohorts.

Allergo J Int 2014; 23: 96−112 105

tus asthmaticus, when muscular exhaustion occurs, arti� cial ventilation may be necessary [64].

Anaphylaxis with predominant abdominal symptomsAbdominal symptoms are treated in the same way as anaphylaxis with predominant skin symptoms (Fig. 1). Only in the case of insu� cient response to systemically applied antiallergic substances do gas-trointestinal symptoms require speci� c treatment. Nausea, vomiting, as well as abdominal colic repre-sent the relevant symptoms. Antiemetics like meto-clopramide, antihistamines and dimenhydrinate or

the application of a serotonin (5 HTR3) antagonist (e. g. ondansetron) can be considered. For abdomi-nal cramps the intravenous application of butylsco-polamine may have alleviating e� ects.

Anaphylaxis with predominant skin manifestations� e application of an intravenous catheter is the � rst measure of choice. It is recommended to keep the catheter open by infusion of electrolyte solutions. Anti-allergic substances like dimetindene and glu-cocorticosteroids should be given in the usual dose (Fig. 1, Tab. 7).

| Table 6Pharmacotherapy for children, adolescents and adults in intensive care SubstanceSubstance Route of applicationRoute of application < 15 kg bw< 15 kg bw 15–30 kg bw15–30 kg bw 30–60 kg bw30–60 kg bw > 60 kg bw> 60 kg bwAdrenaline Intravenous, bolus¹ 0.1 ml/kg bw

(from 1 mg/10 ml)¹0.1 ml/kg bw(from 1 mg/10 ml)¹

0.05–0.1 ml/kg bw(from 1 mg/10 ml)¹

0.05–0.1 ml/kg bw(from 1 mg/10 ml)¹

Adrenaline Continuous infusion 0.05–1.0 µg/kg/min 0.05–1.0 µg/kg/min 0.05–1.0 µg/kg/min 0.05–1.0 µg/kg/min

Adrenaline Inhaled via nebulizer 2 ml² 2 ml² 2 ml² 2 ml²Dimetindene Intravenous 1 ml³ 2–3 ml³ 4 ml³ 8 ml³ oder

1 ml/10 kg bwPrednisolone Intravenous 50 mg 100 mg 250 mg 250–1000 mgSalbutamolTerbutalin

Inhaled 2 puff s DAper spacer

2 puff s DAper spacer

2–4 puff s DAper spacer

2–4 puff s DAper spacer

Reproterol⁴ Continuous infusion 0,1 µg/kg/min 0,1 µg/kg/min 0,1 µg/kg/min 0,1 µg/kg/minVolume Bolus (0,9 % NaCl) 20 ml/kg bw 20 ml/kg bw 10–20 ml/kg bw 10–20 ml/kg bwVolume Infusion

(electrolyte solution)1 to 2 ml/kg/min 1 to 2 ml/kg/min 1 to 2 ml/kg/min 1 to 2 ml/kg/min

Oxygen Inhaled 2 to 10 l/min 5 to 12 l/min 5 to 12 l/min 5 to 12 l/min¹ For the application of a bolus a 1 mg/ml adrenaline solution is diluted (1 ml plus 9 ml 0.9 % NaCl) to a fi nal concentration of 0.1 mg/ml); ¹ For the application of a bolus a 1 mg/ml adrenaline solution is diluted (1 ml plus 9 ml 0.9 % NaCl) to a fi nal concentration of 0.1 mg/ml); ¹² For inhalation the original concentration is used (1 mg/ml); ² For inhalation the original concentration is used (1 mg/ml); ²³ of the (original) concentration of 1 mg/ml (1 ml = 1 mg); ³ of the (original) concentration of 1 mg/ml (1 ml = 1 mg); ³⁴ Reproterol can also be given as bolus⁴ Reproterol can also be given as bolus⁴

bw, body weight

| Table 7Pharmacotherapy for children, adolescents and adults under out-patient conditions SubstanceSubstance Route of applicationRoute of application < 15 kg bw< 15 kg bw 15–30 kg bw15–30 kg bw > 30–60 kg bw> 30–60 kg bw > 60 kg bw> 60 kg bwAdrenaline Intramuscular 0.01 ml/kg bw

(1 mg/1 ml)0.01 ml/kg bw(1 mg/1 ml)

0.01 ml/kg bw(1 mg/1 ml)

0.01 ml/kg bw(1 mg/1 ml)

Adrenaline Autoinjector i.m. see i.m. 150 µg 300 µg 300–600 µg

Adrenaline Inhaled via nebulizer 2 ml² 2 ml² 2 ml² 2 ml²Adrenaline Intravenous bolus1 0.1 ml/kg bw

(of 1 mg/10 ml)¹0.1 ml/kg bw(of 1 mg/10 ml)¹

0,05–0,1 ml/kg bw(of 1 mg/10 ml)¹

0,05–0,1 ml/kg bw(of 1 mg/10 ml)¹

Dimetindene Intravenous 1 ml³ 1 ml/10 kg bw³(max. 4 ml)

1 ampule = 4 ml³ 1–2 ampule = 4–8 ml³ (1 ml/10 kg bw)

Prednisolone Intravenous 50 mg 100 mg 250 mg 500-1000 mgSalbutamolTerbutalin

Inhaled 2 hubs DAper spacer

2 hubs DAper spacer

2–4 hubs DAper spacer

2–4 hubs DAper spacer

Volume Bolus (NaCl 0.9 %) 20 ml/kg bw 20 ml/kg bw 10–20 ml/kg bw 10–20 ml/kg bwVolume Infusion

(Ringer solution)1 to 2 ml/kg/min 1 to 2 ml/kg/min 1 to 2 ml/kg/min 1 to 2 ml/kg/min

Oxygen Inhaled 2 to 10 l/min 5 to 12 l/min 5 to 12 l/min 5 to 12 l/min¹ For the application of a bolus a 1 mg/ml adrenaline solution is diluted (1 ml plus 9 ml 0.9 % NaCl) to a fi nal concentration of 0.1 mg/ml); ¹ For the application of a bolus a 1 mg/ml adrenaline solution is diluted (1 ml plus 9 ml 0.9 % NaCl) to a fi nal concentration of 0.1 mg/ml); ¹² For inhalation application the original concentration is used (1 mg/ml)² For inhalation application the original concentration is used (1 mg/ml)²³ of a (original) concentration of 1 mg/ml (1 ml = 1 mg) ³ of a (original) concentration of 1 mg/ml (1 ml = 1 mg) ³

bw, body weight

106 Allergo J Int 2014; 23: 96−112

Guideline Acute therapy and management of anaphylaxis

Management of therapy control� e observation of the anaphylaxis patient until he/she is in de� nite long-lasting remission is crucial (Fig. 1). � e possibility of a biphasic course of ana-phylaxis has to be kept in m-ind. � erefore in all se-vere anaphylactic reactions (grade II grade II and higher) in-patient hospital observation is indicated. In anaphylaxis with life-threatening systemic reac-tions monitoring in an intensive care unit is recom-mended. On discharge the indication for the pre-scription of an emergency set for self-treatment (adrenaline auto-injector, antihistamines, glucocor-ticosteroids and possibly a topical bronchodilatory aerosol spray) should be considered. � e practical use of the emergency equipment for self-treatment

– especially the application of the epinephrine auto-injector – should be trained via educational pro-grams (Tab. 8; see below). � e referral to an allergist for further diagnostic work-up and possible long-term therapy is necessary. In order to gather infor-mation on triggers, associated circumstances and co-factors of anaphylaxis, an anaphylaxis registry has been installed in Germany where physicians can report severe anaphylactic reactions online (www.anaphylaxie.net).

Special considerations in childhoodWith regard to dosing of certain drugs in the treat-ment of anaphylaxis the particular dosages for children have to be considered.

Patient management and self-medicationTarget groupEach patient who has su� ered from an anaphylaxis must be informed about the most important beha-vioral steps that may help in the prevention and treatment of anaphylaxis. � is is particularly im-portant for patients with an increased risk of ana-phylaxis like adults with mastocytosis or a prog-nostically signi� cant symptom constellation. � is

is equally important when the patient successfully undergoes allergen-speci� c immunotherapy (ASIT), e.g. against insect venoms.

Self-medication ("emergency set for self-help")Basically all patients who have survived an anaphy-laxis and cannot avoid with certainty the elicitor as well as all adult patients with mastocytosis should be prescribed an “emergency set for self-help” [65, 66]. In Germany, Austria and Switzerland common-ly the following drugs are included in the emergen-cy set: an adrenaline autoinjector, H1 antihistamine, glucocorticosteroid and for patients with asthma, an inhaled bronchodilator (Tab. 8). Each patient with an “emergency set for self-help” must be remin-ded to always carry the set with him/her. He/she must be informed about the correct storage and shelf life of the substances as well as possible seda-tive side e� ects caused by older antihistamines (in-� uence on driving performance). Patients as well as persons in their social network – in the case of children parents and caretakers – must be instruc-ted in the use of the medication. For this standar-dized anaphylaxis emergency plans are available.

Several adrenaline autoinjectors preparations, that apply various single doses (150 µg for patients of 15–30 kg bw, 300 µg for patients over 30 kg bw), are available for intramuscular injection. � ere is information, that in otherwise healthy children with a body weight between 10 and 15 kg, the dose of 150 μg is not hazardous. Parents must be infor-med about o� -label use in this indication. � e available adrenaline autoinjectors di� er in their practical administration: Patients receiving a se-cond or subsequent autoinjector, should be prescri-bed a preparation requiring the same administrati-on technique. In order to train patients and their social environment in the application of the autoin-jector, it is helpful to give them a dummy (without needle) and to motivate them to practice frequently.

| Table 8Ingredients of an "emergency set for self-help" for patientsSubstanceSubstance Route of application and dosageRoute of application and dosageAdrenaline Autoinjector for intramuscular application,

adapted to body weight:> 15 kg 150 µg adrenaline> 30 kg 300 µg adrenaline

H1 antihistamine According to age and preference of patients as liquid or fast-melt tablet. The licensed daily dose of the respective antihistamine is recommended as single dose. Dimetindene drops can be taken orally in a dosage adapted for bodyweight and corresponding to the intravenous dose.

Glucocorticosteroid According to age and preference of the patient oral or rectal (tablets or liquid) with 50–100 mg Prednisolone equivalent.

Optional In patients with bronchial asthma: β2 adrenoceptor agonists When airway obstruction can be expected an adrenaline preparation for inhalation with spray head (to be ordered especially from the pharmacist)

Note: “The emergency set for self-help” should contain written instructions for the application of its constituents (e.g. anaphylaxis-passport and/or anaphylaxis-emergency plan)

Allergo J Int 2014; 23: 96−112 107

In the selection of an H1 antihistamine, the ease with which it can be swallowed and individual pre-ferences should be considered regarding the appli-cation form (drops for small children, tablets or fast-melt tablets for older children or adults). If di� cul-ty in swallowing prevails (laryngeal angioedema), liquid applications are to be preferred. � e same cri-teria are valid for glucocorticosteroids, whereby rec-tal application should also be considered.

In asthma patients, additional inhaled β receptor agonists should prescribed and when there is a his-tory of laryngeal edema adrenaline for inhalation.

Patients supplied with an emergency set for self-help must be shown how to administer the medica-tion and also receive written information regarding this. Not all patients having su� ered an immediate-type allergic reaction need an emergency set or au-toinjector. � ere is no need, when the elicitor is known and easily avoided like in drug-induced ana-phylaxis. Also a� er allergen-speci� c immunothera-py with insect venom, patients without additional risk factors, have no increased risk for anaphylaxis compared to the normal population. It is therefore

not compulsory for these patients to continuously carry self-medication with them. Indications for the prescription of an adrenaline autoinjector are listed in Tab. 9. Occasionally (e.g. very severe anaphylaxis, high body weight, mastocytosis, long distance to medical care) the prescription of a second autoin-jector is advisable.

In addition to the emergency set for self-help an “anaphylaxis passport” should be issued which, apart from the elicitors, also contains the dosage of drugs and application of the drugs dependent upon the re-action.

Practical emergency managementMost anaphylactic emergencies occur at home. � erefore information on emergency self-manage-ment has to include all measures that have to be per-formed by the patient him-/herself or by his/her im-mediate surroundings. � e patient should be trai-ned in

— the recognition of an anaphylactic reaction —symptom-orientated self-medication —correct positioning

| Table 9Indications for the prescription of an adrenaline autoinjector

— Patients with a systemic allergic reaction and bronchial asthma (even without a history of anaphylaxis)Patients with a systemic allergic reaction and bronchial asthma (even without a history of anaphylaxis)

— Progressive severity of symptoms of a systemic allergic reaction

— History of previous anaphylactic reactions to elicitors which cannot be avoided with certainty

— Systemic allergy to potent allergens e.g. peanuts, tree nuts, sesame

— High degree of sensitization, e.g. patients who react to even minute amounts of allergen

— Adults with mastocytosis (even without a history of anaphylaxis)

| Table 10Recommendations for long term management for prevention of anaphylaxis and self-medication A) PreventionA) Prevention1. Issuing of an anaphylaxis passport und anaphylaxis emergency plan2. Emergency set, anaphylaxis-passport and mobile phone should always be at hand 3. Knowledge of the symptoms of anaphylaxis and being able to distinguish them from other symptoms (e.g. fear)4. If possible autonomous training with the adrenalin-autoinjector (dummy without needle and drug) to be repeated every 3–6

months (cave: do not mix up with the “real” autoinjector!) 5. Shelf life of substances has to be checked regularly. For the Adrenalin-autoinjector the reminder service of the producing compa-

ny can be used. 6. Inform the social network: organize support, delegate tasks for emergency situation (emergency call, application of drugs, recei-

ving the emergency physician etc.)7. Possibly further counseling, information material and exchange with other patients via patient organizations (e.g. Deutscher All-

ergie- und Asthmabund daab, mastocytosis self help group, anaphylaxis education in small groups according to anaphylaxis group education and training AGATE in Germany)

B) Emergency self-treatment8. Application of the emergency set (see Anaphylaxis-passport / Anaphylaxis emergency plan)9. Positioning

a) with predominant heart and cardiovascular symptoms: lying down, legs up (shock positioning)b) with predominant respiratory symptomatology; sitting ("coachman position")c) when there is unconsciousness: recovery position

10. Emergency telephone number: EU 112 (CH 144), the word "anaphylaxis/anaphylactic shock" should be mentioned fi rst, the con-versation should be guided by the rescue central offi ce

11. Ask for help and support from the social surrounding

108 Allergo J Int 2014; 23: 96−112

Guideline Acute therapy and management of anaphylaxis

—making an emergency call (telephone no. 112 in D and A, 144 in CH). � e word “anaphylaxis/ana-phylactic shock” should be mentioned � rst, the conversation should then be guided by the rescue centre.

Potential suspected elicitors (foods, insects, drugs) should be preserved if possible.

Self-medication should be taken depending on symptoms and certainty of allergen contact. It is essential that patients receive information on when to take which medications as here o� en an uncertainty prevails in patients and their relatives. When there has been a de� nite contact with an elicitor of anaphylaxis (e.g. insect sting without preceding allergen-speci� c immunotherapy or consumption of allergy-inducing foods or intake of allergy-eliciting drugs), the anaphylaxis emer-gency plan (Fig. 2) must be followed. � e imme-diate application of oral drugs is recommended even if the patient is asymptomatic. � e emergen-cy plan and anaphylaxis passport are important aids (Fig. 2).

Long-term therapy and prevention managementA� er an attack of anaphylaxis, allergy diagnostics should be performed. � e identi� cation of the elicitor, the targeted issuing of an anaphylaxis passport and individual counseling regarding risks and dangers are the necessary basis for all preventive measures (Tab. 10). Diagnostics com-prise all methods allowing the doubtless identi� -cation of an elicitor. Relevant risk factors for ana-phylaxis (e.g. asthma, mastocytosis or medication with certain drugs) should be identi� ed and their signi� cance explained to the patient. If possible, allergen-speci� c immunotherapy should be star-ted [24]. In the case of recurrent anaphylactic re-actions regular monitoring and long-term phar-macotherapy (e.g. anti-IgE, omalizumab) should be considered [67].

Elicitor-speci� c preventionPatients with food allergy as elicitor of anaphylaxis should get complete information and nutritional counseling regarding the identi� cation and possib-le avoidance from the eliciting food by an experi-enced nutritionist (www.ak-dida.de, www.daab.de). � is should comprise information regarding alter-native food choises and advice on preventing poten-tial nutritional de� ciencies when consequent avoi-dance of the culprit food is necessary. In particular patients should be informed about recent food de-claration regulations and their implications, in or-der to allow for the low risk purchase of foods e.g. at the supermarket and when eating out. In patients with insect venom allergy precautionary strategies for the avoidance of repeated stings have to be dis-

cussed; in patients with drug allergy the risk of cross-reactions to related substances and the prob-lem of synonyms should be mentioned.

Counseling, educational programs and helpful toolsIn order to communicate all the necessary theore-tical and practical information, educational pro-grams as they have been developed by the “Arbeits-gemeinscha� Anaphylaxie Training und Edukation (AGATE)” (Working Group Anaphylaxis Education and Training), have proven helpful [68, 69]. Various target groups (adult patients, parents of children at risk of anaphylaxis, children, adolescents, child care workers and teachers) are trained in interdiscipli-narily guided group sessions on how to behave in case of anaphylaxis. Equally, seminars for education of “anaphylaxis trainers” (train-the-trainer semi-nars) are o� ered (www.anaphylaxieschulung.de).

© German Allergy and Asthma Association · Fliethstr. 114 · 41061 Mönchengladbach · www.daab.de · 02161 - 814940

Anaphylaxis Action Plan

Photo

Name:

Date of birth:

Confirmed allergens, that cause anaphylaxis

Asthma? Yes (higher risk for a severe reaction) No

Family emergency contact: name / phone

Where is emergency medication stored?

Plan prepared by (physician):

Date / Signature

How to administer the adrenaline autoinjector

Sticker with instructions

how to use prescribed adrenaline

autoinjector

Mild to moderate allergic reactionSigns and symptoms• Tingling mouth and throat• Itching on palms, soles or genital area• Redness of the skin• Wheals, hives• Swelling of lips and face• Nausea, vomiting• Feeling of impending doom

First Aid Action1. Stay with the patient/ child. Call for help: 112

(ambulance and inform emergency contact)2. Give antihistamine and corticosteroid

Name and dose of antihistamine

Name and dose of corticosteriod

3. Locate adrenaline autoinjector and watch patient for further signs and symptoms of anaphylaxis

Severe reactionSigns and symptoms• Sudden hoarseness • Wheezing• Shortness of breath • Loss of consciousness• Combination of two or more symptoms from

different body areas (skin, gastrointestinal tract, respiratory system, cardiovascular system) e.g. abdominal pain and skin-reaction

• Any (even mild) reaction, after definite allergen contact (e.g. eating allergenic food or being stung by bee or wasp)

First Aid Action1. Administer adrenaline autoinjector into outer mid-thigh

Name of adrenaline autoinjector

2. Position of patient:– with respiratory symptoms: sit or position of comfort– with cardiovascular symptoms while conscious: lay flat– unconscious: recovery position

3. If short of breath (airway symptoms) administer asthma reliever (blue inhaler) in addition

Name of asthma reliever

4. Call for help: 112 (ambulance and ask for emergency and ask for emergency and ask forphysician)

5. Inform emergency contact (see left)6. Give antihistamine and corticosteroid in

addition (see above)

Published by: Endorsed by:

Fig. 2: Anaphylaxis emergency plan (available at info@daab.de)

Allergo J Int 2014; 23: 96−112 109

Following allergy diagnostics it is helpful to inform patients and their relatives of patient organizations (www.daab.de, www.mastozytose.de) which are ex-perienced in the further counseling of patients with regard to coping with the disease in everyday life. � ey also provide information material and helpful tools such as restaurants cards, preprints of relevant travel documents, liability exclusion and cards with emergency telephone numbers.

Prof. Dr. med. Dr. phil. Johannes RingDept. Dermatology and Allergology BiedersteinChristine Kuehne-Center Allergy Research and Education (CK-CARE)Technical University MunichBiedersteinerstr. 2980802 MunichGermanyEmail: johannes.ring@lrz.tum.de

Cite this as: Ring J, Beyer K, Biedermann T, Bircher A, Duda D, Fischer J et al. Guideline for acute the-rapy and management of anaphylaxis – S2 Guide-line of DGAKI, AeDA, GPA, DAAU, BVKJ, ÖGAI, SGAI, DGAI, DGP, DGPM, AGATE and DAAB. Allergo J Int 2014; 23: 96–112DOI 10.1007/s40629-014-0009-1

Con� ict of Interest The authors declare that there is no con� ict of interest. More detailed information can be seen on the AWMF website (www.awmf.org).

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